The present invention, relates to novel crystalline forms of pharmaceutically active agents and, more particularly, but not exclusively, to novel crystalline forms of chemical conjugates comprised of a psychotropic drug and an organic acid, to processes of producing the same and to uses thereof in the treatment of CNS diseases and disorders.
A series of conjugates of psychotropic drugs and organic acids and their use in the treatment of psychotropic and/or proliferative diseases and disorders are described in detail in International Patent Applications published as WO 03/026563 and WO 2005/092392 and in U.S. Pat. No. 7,544,681, which are all incorporated by reference as if fully set forth herein. These conjugates may exert greater therapeutic efficacy and/or cause fewer and/or less severe side effects than their respective non-conjugated psychotropic drugs. Among the disclosed conjugates is a conjugate that comprises perphenazine covalently linked to γ-aminobutyric acid (GABA).
Acid addition salts of such conjugates in which the organic acid has a free amino group (such as GABA and other GABA agonists) have been disclosed in WO 2006/131923. Among the disclosed salts is a mesylate addition salt of the perphenazine-GABA conjugate prepared by reacting a solution of an N-protected perphenazine-GABA conjugate with methanesulfonic acid to afford, upon filtration, the mesylate salt, having a purity of about 98% according to HPLC measurements.
Crystalline forms, that include polymorphs and pseudopolymorphs, are distinct solids sharing the same structural formula, yet having different physical properties due to different conformations and/or orientations of the molecule in the unit cell of the crystal. The physical characteristics, such as solubility and stability, of different crystalline forms are often different and are thus exceptionally relevant in the field of pharmacology.
For a general review of crystalline forms (i.e. polymorphs and pseudopolymorphs) and the pharmaceutical applications of crystalline forms see Wall Pharm. Manuf. 1986, 3, 33; Haleblian et al. J. Pharm. Sci. 1969, 58, 911; and Haleblian J. Pharm. Sci., 1975, 64, 1269.
Different crystalline forms of a pharmaceutically useful compound provide opportunities to improve the performance characteristics of a pharmaceutical product. Different crystalline forms enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a desired release profile, solubility characteristics or other desired characteristic. It is well known that new crystalline forms of known useful compounds are of utility.